Traditional approaches to administration of drugs and other therapeutic agents for the treatment of disease often use a systemic route. This exposes pathologic cell populations and normal tissues nonspecifically to these agents. If active agents for a given disease have only a low therapeutic index, treatment may either be ineffective or be associated with serious side effects. This situation obtains for a wide range of malignancies (such as cancers of the lung, breast, prostate and colon), as well as for a variety of immune-mediated and inflammatory conditions. Among these latter conditions are disease states such as autoimmune diabetic states, organ transplantation, bone marrow transplantation, inflammatory bowel disease, and other autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis). The problem is addressed in this application with an innovative approach to intracellular delivery of drugs or other agents that could ultimately be applied to the diagnosis and therapy of the diseases listed above. This approach involves the utilization of fusion molecule consisting of a single chain monoclonal antibody and the ligand-binding domain of selected cytokine receptors. This fusion protein will be used to target pathogenic cell populations. Therapeutic or diagnostic agents linked to the cognate cytokine will then be given. This capitalizes on the specificity of the ligand/receptor interactions; the rapid, efficient internalization of these receptors, and allows for a high-level cell surface antigen to be targeted to substantially increase the number of cytokine receptors over their low background level. This application, specifically, seeks to advance the initial efforts made by researchers by constructing and expressing antibody-receptor fusion proteins as well as armed forms of the cognate ligands. After construction and expression, their function will be tested in vitro on an ultimate path towards pre-clinical and clinical evaluation in a variety of disease models and conditions.
